EP3330257B1 - Dérivés de la pyrimidine pour le traitement des infections virales - Google Patents

Dérivés de la pyrimidine pour le traitement des infections virales Download PDF

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Publication number
EP3330257B1
EP3330257B1 EP17203628.7A EP17203628A EP3330257B1 EP 3330257 B1 EP3330257 B1 EP 3330257B1 EP 17203628 A EP17203628 A EP 17203628A EP 3330257 B1 EP3330257 B1 EP 3330257B1
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compound
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ppm
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dmso
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EP3330257A1 (fr
Inventor
David Craig Mc Gowan
Pierre Jean-Marie Bernard Raboisson
Werner Constant J. EMBRECHTS
Tim Hugo Maria Jonckers
Stefaan Julien Last
Serge Maria Aloysius Pieters
Jaromir Vlach
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Janssen Sciences Ireland ULC
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Janssen Sciences Ireland ULC
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Priority to RS20200465A priority Critical patent/RS60191B1/sr
Priority to MEP-2020-84A priority patent/ME03782B/fr
Priority to PL17203628T priority patent/PL3330257T3/pl
Priority to SI201231762T priority patent/SI3330257T1/sl
Priority to SM20200196T priority patent/SMT202000196T1/it
Priority to DK19192173.3T priority patent/DK3590928T3/da
Priority to PL19192173T priority patent/PL3590928T3/pl
Priority to EP19192173.3A priority patent/EP3590928B1/fr
Application filed by Janssen Sciences Ireland ULC filed Critical Janssen Sciences Ireland ULC
Publication of EP3330257A1 publication Critical patent/EP3330257A1/fr
Publication of EP3330257B1 publication Critical patent/EP3330257B1/fr
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Priority to HRP20200538TT priority patent/HRP20200538T1/hr
Priority to CY20211100767T priority patent/CY1124469T1/el
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating viral infections, like HBV or HCV.
  • the present invention relates to the use of pyrimidine derivatives in the treatment of viral infections, immune or inflammatory disorders, whereby the modulation, or agonism, of toll-like-receptors (TLRs) is involved.
  • TLRs toll-like-receptors
  • Toll-Like Receptors are primary transmembrane proteins characterized by an extracellular leucine rich domain and a cytoplasmic extension that contains a conserved region.
  • the innate immune system can recognize pathogen-associated molecular patterns via these TLRs expressed on the cell surface of certain types of immune cells. Recognition of foreign pathogens activates the production of cytokines and upregulation of co-stimulatory molecules on phagocytes. This leads to the modulation of T cell behaviour.
  • TLR1 to TLR13 TLRs
  • TLR1 to TLR13 TLRs
  • equivalent forms of many of these have been found in other mammalian species.
  • equivalents of certain TLR found in humans are not present in all mammals.
  • a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus.
  • mice express TLRs 11, 12, and 13, none of which are represented in humans.
  • Other mammals may express TLRs which are not found in humans.
  • Other non-mammalian species may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the process of using experimental animals as models of human innate immunity.
  • interferon In the treatment of certain viral infections, regular injections of interferon (IFN ⁇ ) can be administered, as is the case for hepatitis C virus (HCV), ( Fried et. al. Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82 ).
  • HCV hepatitis C virus
  • IFN inducers offer the potential advantages of reduced immunogenicity and convenience of administration.
  • novel IFN inducers are potentially effective new class of drugs for treating virus infections.
  • IFN inducer having antiviral effect see De Clercq, E.; Descamps, J.; De Somer, P. Science 1978, 200, 563-565 .
  • IFN ⁇ is also given in combination with other drugs in the treatment of certain types of cancer ( Eur. J. Cancer 46, 2849-57 , and Cancer Res. 1992, 52, 1056 ).
  • TLR 7/8 agonists are also of interest as vaccine adjuvants because of their ability to induce pronounced Th1 response ( Hum. Vaccines 2010, 6, 1-14 ; Hum. Vaccines 2009, 5, 381-394 ).
  • a compound of formula (I) is provided or a pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof, wherein
  • the present invention provides compounds of formula (I) wherein R 3 is butyl or pentyl and wherein R 2 and R 1 are as specified above.
  • the invention concerns compounds of formula (I) wherein R 3 is C 4-8 alkyl substituted with hydroxyl, and wherein R 2 and R 1 are as specified above.
  • R 3 when being C 4-8 alkyl substituted with hydroxyl, is one of the following
  • the present invention also provides compounds of formula (I) wherein R 1 is hydrogen or -CH 3 and wherein R 2 and R 3 are as specified above.
  • the present invention provides compounds of formula (I) wherein wherein R 2 is arylalkyl or heteroarylalkyl, substituted with C 1-3 alkyl, hydroxyl, alkoxy, nitrile, heterocycle or ester and wherein R 1 and R 3 are as specified above.
  • the current invention concerns compounds of formula (I) wherein R 2 is C 1-3 alkyl substituted by aryl, heterocycle, or heteroaryl which is further substituted by C 1-3 alkyl, alkoxy, carboxylic ester or carboxylic amide and wherein R 1 and R 3 are as specified above
  • the preferred compounds according to the invention are:
  • the compounds of formula (I) and their pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof have activity as pharmaceuticals, in particular as modulators of Toll-Like Receptors (especially TLR7 and/or TLR8) activity.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof according to the current invention, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used as a medicament.
  • the compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, or said pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used in the treatment of a disorder or disease in which the modulation of TLR7 and /or TLR8 is involved.
  • alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkenyl refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond.
  • alkynyl refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • cycloalkyl refers to a carbocyclic ring containing the specified number of carbon atoms.
  • heteroaryl means an aromatic ring structure as defined for the term “aryl” comprising at least 1 heteroatom selected from N, O and S, in particular from N and O.
  • aryl means an aromatic ring structure optionally comprising one or two heteroatoms selected from N, O and S, in particular from N and O.
  • Said aromatic ring structure may have 4, 5, 6 or 7 ring atoms.
  • said aromatic ring structure may have 5 or 6 ring atoms.
  • bicyclic heterocycle means an aromatic ring structure, as defined for the term “aryl” comprised of two fused aromatic rings. Each ring is optionally comprised of heteroatoms selected from N, O and S, in particular from N and O.
  • arylalkyl means an aromatic ring structure as defined for the term “aryl” optionally substituted with an alkyl group.
  • heteroarylalkyl means an aromatic ring structure as defined for the term “heteroaryl” optionally substituted by an alkyl group.
  • alkoxy refers to an alkyl (carbon and hydrogen chain) group singular bonded to oxygen like for instance a methoxy group or ethoxy group.
  • Heterocycle refers to molecules that are saturated or partially saturated and include ethyloxide, tetrahydrofuran, dioxane or other cyclic ethers.
  • Heterocycles containing nitrogen include, for example azetidine, morpholine, piperidine, piperazine, pyrrolidine, and the like.
  • Other heterocycles include, for example, thiomorpholine, dioxolinyl, and cyclic sulfones.
  • Heteroaryl groups are heterocyclic groups which are aromatic in nature. These are monocyclic, bicyclic, or polycyclic containing one or more heteroatoms selected from N, O or S. Heteroaryl groups can be, for example, imidazolyl, isoxazolyl, furyl, oxazolyl, pyrrolyl, pyridonyl, pyridyl, pyridazinyl, or pyrazinyl.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Suitable base salts are formed from bases which form non-toxic salts.
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • polymorph refers to the ability of the compound of the invention to exist in more than one form or crystal structure.
  • the compounds of the present invention may be administered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral, rectal, or percutaneous administration.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Also included are solid form preparations that can be converted, shortly before use, to liquid forms.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • the compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective amount ranges mentioned above are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
  • Intermediate G is then combined, with or without base, with guanidine carbonate in an appropriate solvent, for example, ethanol.
  • Intermediate H is then reacted with phosphorous oxychloride to form the chloropyrimidine intermediate (J).
  • the products are then formed as a result of heating (J) in the presence of excess amine and optionally excess organic base, for example triethylamine, at elevated temperature.
  • This is a general scheme using methods known to a skilled person, see for instance Organic Syntheses volume 33, p.43 (1953 ).
  • guanidine carbonate [593-85-1] (111.31 g, 0.618 mol) was treated with a sodium ethoxide solution, freshly prepared by the careful addition of Na (28.41 g, 1.24 mol) to anhydrous ethanol (750 mL) at room temperature.
  • the resulting pale yellow reaction mixture was heated to reflux for 15 hours.
  • the solvent was removed, and then the crude residue was dissolved in water (1.5 L).
  • the solid was collected, washed extensively with water and ethanol to give intermediate B-1 (160 g).
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate twice.
  • the organic layer was washed with brine and dried over sodium sulfate.
  • the solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure.
  • the crude was purified via silica column chromatography using a heptane to ethyl acetate gradient to afford a pale yellow oil, G-1.
  • AA-2 200 g, 532 mmol
  • the solvents were evaporated and the residue was diluted in petroleum ether and filtered.
  • the solvents of the filtrate were removed under reduced pressure and the residue was purified by silica chromatography using a petroleum ether to 3% ethyl acetate in petroleum ether gradient to give AA-3 (90 g) as a colorless oil.
  • n-butyl lithium (290mL, 725mmol, 1.5eq.) was added to a stirred solution of AA-4 (165 g, 781 mmol) in THF (800 mL) at -78°C.
  • the reaction mixture was stirred for 30 minutes then AA-3 (90 g, 488.4 mmol) in THF (400 mL) was added and the reaction was stirred for 2 hours at -78°C.
  • the mixture was quenched with sat., aq. NH 4 Cl solution and warmed to room temperature.
  • the product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated.
  • AA-5 (130 g, 328 mmol) was dissolved in THF (1.5 L) and LAH (20 g, 526 mmol) was added at 0°C in small portions. The resulting mixture was stirred at the same temperature for 2 hours and then allowed to warm to room temperature. The mixture was quenched with a sat. aq. NH 4 Cl solution. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The combined organic layers were dried over sodium sulfate, the solids were removed via filtration and concentrated to afford crude AA-6 (100 g), which was used in the next step without further purification.
  • AA-10 was prepared according to the preparation of AA-9, using butyraldehyde instead of valeraldehyde.
  • the crude mixture was purified by Prep HPLC on (RP Vydac Denali C18 - 10 ⁇ m, 250 g, 5 cm).
  • Mobile phase 0.25% NH 4 OAc solution in water, methanol
  • SCX acid modified solid phase extraction cartridge
  • Method A Waters Aquity UPLC equipped with a PDA detector (210-400 nm) and a Waters SQD with a dual mode ion source ES+/-.
  • the column used was a Halo C18, 2.7 ⁇ m, 2.1 x 50 mm, heated to 50°C.
  • a gradient of 95% aqueous formic acid (0.1 %)/5% acetonitrile to 100% acetonitrile was ramped over 1.5 minutes, held for 0.6 minutes, then returns to 100% aqueous formic acid (0.1%) for 0.5 minutes.
  • the flow rate was 0.6 mL/min.
  • Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 ⁇ m, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min.
  • Two mobile phases (10 mM ammonium acetate in H 2 O/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.7 minutes. An injection volume of 0.75 ⁇ l was used.
  • Cone voltage was 30 V for positive ionization mode and 30 V for negative ionization mode.
  • MS Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an electrospray ionization source.
  • the capillary needle voltage was 3 kV and the source temperature was maintained at 140 °C.
  • Nitrogen was used as the nebulizer gas.
  • Xterra MS C18 column (3.5 ⁇ m, 4.6 x 100 mm) with a flow rate of 1.6 mL/min.
  • mobile phase A 95% 25 mM ammoniumacetate + 5 % acetonitrile
  • mobile phase B acetonitrile
  • mobile phase C methanol
  • Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 ⁇ m, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 mL/min.
  • Two mobile phases (mobile phase A: 10mM ammonium acetate in H 2 O/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.2 minutes. An injection volume of 0.5 ⁇ l was used.
  • Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
  • TLR7 and/or TLR8 The ability of compounds to activate human TLR7 and/or TLR8 was assessed in a cellular reporter assay using HEK293 cells transiently transfected with a TLR7 or TLR8 expression vector and NF ⁇ B-luc reporter construct.
  • the TLR expression construct expresses the respective wild type sequence or a mutant sequence comprising a deletion in the second leucine-rich repeat of the TLR.
  • Such mutant TLR proteins have previously been shown to be more susceptible to agonist activation ( US 7498409 ).
  • HEK293 cells were grown in culture medium (DMEM supplemented with 10% FCS and 2 mM Glutamine).
  • culture medium DMEM supplemented with 10% FCS and 2 mM Glutamine.
  • cells were detached with Trypsin-EDTA, transfected with a mix of CMV-TLR7 or TLR8 plasmid (750 ng), NF ⁇ B-luc plasmid (375 ng) and a transfection reagent and incubated for 48 hours at 37°C in a humidified 5% CO 2 atmosphere.
  • Transfected cells were then detached with Trypsin-EDTA, washed in PBS and resuspended in medium to a density of 1.67 x 10 5 cells/mL.
  • Compound toxicity was determined in parallel using a similar dilution series of compound with 30 ⁇ L per well of cells transfected with the CMV-TLR7 construct alone (1.67 x 10 5 cells/mL), in 384-well plates. Cell viability was measured after 6 hours incubation at 37°C, 5% CO 2 by adding 15 ⁇ L of ATP lite (Perkin Elmer) per well and reading on a ViewLux ultraHTS microplate imager (Perkin Elmer). Data was reported as CC 50 .
  • Activation of human TLR7 results in robust production of interferon by plasmacytoid dendritic cells present in human blood.
  • the potential of compounds to induce interferon was evaluated by looking at the antiviral activity in the HCV replicon system upon incubation with conditioned media from peripheral blood mononuclear cells (PBMC).
  • PBMC peripheral blood mononuclear cells
  • the HCV replicon assay is based on a bicistronic expression construct, as described by Lohmann et al. (Science (1999) 285: 110-113 ; Journal of Virology (2003) 77: 3007-15 3019 ) with modifications described by Krieger et al. (Journal of Virology (2001) 75: 4614-4624 ).
  • the assay utilized the stably transfected cell line Huh-7 luc/neo harboring an RNA encoding a bicistronic expression construct comprising the wild type NS3-NS5B regions of HCV type 1b translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter gene (Firefly-luciferase) and a selectable marker gene (neoR, neomycine phosphotransferase).
  • IRS Internal Ribosome Entry Site
  • EMCV encephalomyocarditis virus
  • neoR neomycine phosphotransferase
  • the construct is flanked by 5' and 3' NTRs (non-translated regions) from HCV type 1b.
  • PBMCs were prepared from buffy coats of at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 10 5 cells/well were dispensed into 384-well plates containing compounds (70 ⁇ L total volume). After overnight incubation, 10 ⁇ L of supernatant was transferred to 384-well plates containing 2.2 x 10 3 replicon cells/well in 30 ⁇ L (plated the day before).
  • the potential of compounds to induce IFN-I was also evaluated by measuring the activation of interferon-stimulated responsive elements (ISRE) by conditioned media from PBMC.
  • ISRE interferon-stimulated responsive elements
  • the ISRE element of sequence GAAACTGAAACT is highly responsive to the STAT1-STAT2-IRF9 transcription factor, activated upon binding of IFN-I to their receptor IFNAR (Clontech, PT3372-5W).
  • the plasmid pISRE-Luc from Clontech contains 5 copies of this ISRE element, followed by the firefly luciferase ORF.
  • a HEK293 cell line stably transfected with pISRE-Luc (HEK-ISREluc) was established to profile of the conditioned PBMC cell culture media.
  • PBMCs were prepared from buffy coats of at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 10 5 cells/well were dispensed into 384-well plates containing compounds (70 ⁇ L total volume). After overnight incubation, 10 ⁇ L of supernatant was transferred to 384-well plates containing 5 x 10 3 HEK-ISREluc cells/well in 30 ⁇ L (plated the day before).

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Claims (11)

  1. Composé de formule (I)
    Figure imgb1425
     ou sel, tautomère ou ensemble de tautomères, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci, où
    R1 représente un atome d'hydrogène ou un groupement alkyle en C1-4, cyclopropyle, alkoxy en C1-6, halogène, hydroxyle ou trifluorométhyle ;
    R2 représente un groupement alkyle en C1-8, (alkoxy en C1-4)-(alkyle en C1-4), cycloalkyle en C3-7, hétérocycle en C4-7, hétérocycle bicyclique, arylalkyle, hétéroaryle ou hétéroarylalkyle, chacun étant éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi les groupements halogène, hydroxyle, amino, alkyle en C1-6, di-(alkyle en C1-6)-amino, (alkyle en C1-6)-amino, alkyle en C1-6, alkoxy en C1-6, cycloalkyle en C3-6, acide carboxylique, ester carboxylique, amide carboxylique, hétérocycle, aryle, alcényle, alcynyle, arylalkyle, hétéroaryle, hétéroarylalkyle et nitrile ; et
    R3 représente un groupement alkyle en C4-8, alkoxy en C4-8, alcényle en C2-6 ou alcynyle en C2-6, chacun étant éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi les groupements halogène, hydroxyle, amino, alkyle en C1-8, alkoxy en C1-8, cycloalkyle en C3-6 et nitrile.
  2. Composé selon la revendication 1, où R2 représente un groupement alkyle en C1-8, éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi les groupements halogène, hydroxyle, amino, alkyle en C1-6, di-(alkyle en C1-6)-amino, (alkyle en C1-6) -amino, alkyle en C1-6, alkoxy en C1-6, cycloalkyle en C3-6, acide carboxylique, ester carboxylique, amide carboxylique, hétérocycle, aryle, alcényle, alcynyle, arylalkyle, hétéroaryle, hétéroarylalkyle, nitrile.
  3. Composé selon la revendication 2, qui est choisi parmi les composés suivants :
    Figure imgb1426
    Figure imgb1427
    Figure imgb1428
         Composé 1 Composé 2 Composé 4
    Figure imgb1429
    Figure imgb1430
    Figure imgb1431
         Composé 5 Composé 6 Composé 8
    Figure imgb1432
    Figure imgb1433
    Figure imgb1434
         Composé 9 Composé 10 Composé 11
    Figure imgb1435
    Figure imgb1436
    Figure imgb1437
         Composé 12 Composé 13 Composé 14
    Figure imgb1438
    Figure imgb1439
    Figure imgb1440
         Composé 15 Composé 16 Composé 17
    Figure imgb1441
    Figure imgb1442
    Figure imgb1443
         Composé 18 Composé 19 Composé 20
    Figure imgb1444
    Figure imgb1445
    Figure imgb1446
         Composé 21 Composé 22 Composé 23
    Figure imgb1447
    Figure imgb1448
    Figure imgb1449
         Composé 24 Composé 25 Composé 26
    Figure imgb1450
    Figure imgb1451
    Figure imgb1452
         Composé 27 Composé 28 Composé 29
    Figure imgb1453
    Figure imgb1454
    Figure imgb1455
         Composé 30 Composé 31 Composé 32
    Figure imgb1456
    Figure imgb1457
    Figure imgb1458
         Composé 33 Composé 34 Composé 35
    Figure imgb1459
    Figure imgb1460
    Figure imgb1461
         Composé 36 Composé 37 Composé 39
    Figure imgb1462
    Figure imgb1463
    Figure imgb1464
         Composé 40 Composé 41 Composé 42
    Figure imgb1465
    Figure imgb1466
    Figure imgb1467
         Composé 43 Composé 44 Composé 45
    Figure imgb1468
    Figure imgb1469
    Figure imgb1470
         Composé 46 Composé 47 Composé 48
    Figure imgb1471
    Figure imgb1472
    Figure imgb1473
         Composé 49 Composé 50 Composé 51
    Figure imgb1474
    Figure imgb1475
    Figure imgb1476
         Composé 52 Composé 53 Composé 54
    Figure imgb1477
    Figure imgb1478
    Figure imgb1479
         Composé 55 Composé 56 Composé 57
    Figure imgb1480
    Figure imgb1481
    Figure imgb1482
         Composé 58 Composé 59 Composé 60
    Figure imgb1483
    Figure imgb1484
    Figure imgb1485
         Composé 61 Composé 62 Composé 63
    Figure imgb1486
    Figure imgb1487
    Figure imgb1488
         Composé 65 Composé 66 Composé 67
    Figure imgb1489
    Figure imgb1490
    Figure imgb1491
         Composé 68 Composé 69 Composé 70
    Figure imgb1492
    Figure imgb1493
    Figure imgb1494
         Composé 72 Composé 73 Composé 74
    Figure imgb1495
    Figure imgb1496
    Figure imgb1497
         Composé 75 Composé 76 Composé 77
    Figure imgb1498
    Figure imgb1499
    Figure imgb1500
         Composé 78 Composé 79 Composé 80
    Figure imgb1501
    Figure imgb1502
    Figure imgb1503
         Composé 81 Composé 82 Composé 83
    Figure imgb1504
    Figure imgb1505
    Figure imgb1506
         Composé 84 Composé 85 Composé 86
    Figure imgb1507
    Figure imgb1508
    Figure imgb1509
         Composé 87 Composé 88 Composé 89
    Figure imgb1510
    Figure imgb1511
    Figure imgb1512
         Composé 90 Composé 91 Composé 92
    Figure imgb1513
    Figure imgb1514
    Figure imgb1515
         Composé 93 Composé 94 Composé 95
    Figure imgb1516
    Figure imgb1517
    Figure imgb1518
         Composé 96 Composé 97 Composé 98
    Figure imgb1519
    Figure imgb1520
    Figure imgb1521
         Composé 99 Composé 100 Composé 101
    Figure imgb1522
    Figure imgb1523
    Figure imgb1524
         Composé 102 Composé 103 Composé 104
    Figure imgb1525
    Figure imgb1526
    Figure imgb1527
         Composé 105 Composé 106 Composé 107
    Figure imgb1528
    Figure imgb1529
    Figure imgb1530
         Composé 108 Composé 109 Composé 110
    Figure imgb1531
    Figure imgb1532
    Figure imgb1533
         Composé 111 Composé 112 Composé 113
    Figure imgb1534
    Figure imgb1535
    Figure imgb1536
         Composé 114 Composé 115 Composé 116
    Figure imgb1537
    Figure imgb1538
    Figure imgb1539
         Composé 117 Composé 118 Composé 119
    Figure imgb1540
    Figure imgb1541
    Figure imgb1542
         Composé 120 Composé 121 Composé 122
    Figure imgb1543
    Figure imgb1544
    Figure imgb1545
         Composé 123 Composé 124 Composé 125
    Figure imgb1546
    Figure imgb1547
    Figure imgb1548
         Composé 126 Composé 127 Composé 128
    Figure imgb1549
    Figure imgb1550
    Figure imgb1551
         Composé 129 Composé 130 Composé 131
    Figure imgb1552
    Figure imgb1553
    Figure imgb1554
         Composé 132 Composé 133 Composé 134
    Figure imgb1555
    Figure imgb1556
    Figure imgb1557
         Composé 135 Composé 136 Composé 137
    Figure imgb1558
    Figure imgb1559
    Figure imgb1560
         Composé 138 Composé 139 Composé 140
    Figure imgb1561
    Figure imgb1562
    Figure imgb1563
         Composé 141 Composé 142 Composé 143
    Figure imgb1564
    Figure imgb1565
    Figure imgb1566
         Composé 144 Composé 145 Composé 146
    Figure imgb1567
    Figure imgb1568
    Figure imgb1569
         Composé 147 Composé 148 Composé 149
    Figure imgb1570
    Figure imgb1571
    Figure imgb1572
         Composé 150 Composé 151 Composé 152
    Figure imgb1573
    Figure imgb1574
    Figure imgb1575
         Composé 153 Composé 154 Composé 155
    Figure imgb1576
    Figure imgb1577
    Figure imgb1578
         Composé 156 Composé 157 Composé 158
    Figure imgb1579
    Figure imgb1580
    Figure imgb1581
         Composé 159 Composé 160 Composé 161
    Figure imgb1582
    Figure imgb1583
    Figure imgb1584
         Composé 162 Composé 163 Composé 164
    Figure imgb1585
    Figure imgb1586
    Figure imgb1587
         Composé 165 Composé 166 Composé 167
    Figure imgb1588
    Figure imgb1589
    Figure imgb1590
         Composé 168 Composé 169 Composé 170
    Figure imgb1591
    Figure imgb1592
    Figure imgb1593
         Composé 171 Composé 172 Composé 173
    Figure imgb1594
    Figure imgb1595
    Figure imgb1596
         Composé 174 Composé 175 Composé 176
    Figure imgb1597
    Figure imgb1598
    Figure imgb1599
         Composé 177 Composé 178 Composé 179
    Figure imgb1600
    Figure imgb1601
    Figure imgb1602
         Composé 180 Composé 181 Composé 182
    Figure imgb1603
    Figure imgb1604
    Figure imgb1605
         Composé 183 Composé 184 Composé 185
    Figure imgb1606
    Figure imgb1607
    Figure imgb1608
         Composé 186 Composé 187 Composé 188
    Figure imgb1609
    Figure imgb1610
    Figure imgb1611
         Composé 189 Composé 190 Composé 191
    Figure imgb1612
    Figure imgb1613
    Figure imgb1614
         Composé 192 Composé 193 Composé 194
    Figure imgb1615
    Figure imgb1616
    Figure imgb1617
         Composé 195 Composé 196 Composé 197
    Figure imgb1618
    Figure imgb1619
    Figure imgb1620
         Composé 198 Composé 199 Composé 200
    Figure imgb1621
    Figure imgb1622
    Figure imgb1623
         Composé 201 Composé 202 Composé 203
    Figure imgb1624
    Figure imgb1625
    Figure imgb1626
         Composé 204 Composé 205 Composé 206
    Figure imgb1627
    Figure imgb1628
    Figure imgb1629
         Composé 207 Composé 208 Composé 209
    Figure imgb1630
    Figure imgb1631
    Figure imgb1632
         Composé 210 Composé 211 Composé 212
    Figure imgb1633
    Figure imgb1634
    Figure imgb1635
         Composé 213 Composé 214 Composé 215
    Figure imgb1636
    Figure imgb1637
    Figure imgb1638
         Composé 216 Composé 217 Composé 218
    Figure imgb1639
    Figure imgb1640
    Figure imgb1641
         Composé 219 Composé 220 Composé 221
    Figure imgb1642
    Figure imgb1643
    Figure imgb1644
         Composé 222 Composé 223 Composé 224
    Figure imgb1645
    Figure imgb1646
    Figure imgb1647
         Composé 225 Composé 226 Composé 227
    Figure imgb1648
    Figure imgb1649
    Figure imgb1650
         Composé 228 Composé 229 Composé 230
    Figure imgb1651
    Figure imgb1652
    Figure imgb1653
         Composé 231 Composé 232 Composé 233
    Figure imgb1654
    Figure imgb1655
    Figure imgb1656
         Composé 234 Composé 235 Composé 236
    Figure imgb1657
    Figure imgb1658
    Figure imgb1659
         Composé 237 Composé 238 Composé 239
    Figure imgb1660
    Figure imgb1661
    Figure imgb1662
         Composé 240 Composé 241 Composé 242
    Figure imgb1663
    Figure imgb1664
    Figure imgb1665
         Composé 243 Composé 244 Composé 245
    Figure imgb1666
    Figure imgb1667
    Figure imgb1668
         Composé 246 Composé 247 Composé 248
    Figure imgb1669
    Figure imgb1670
    Figure imgb1671
         Composé 249 Composé 250 Composé 251
    Figure imgb1672
    Figure imgb1673
    Figure imgb1674
         Composé 252 Composé 253 Composé 254
    Figure imgb1675
    Figure imgb1676
    Figure imgb1677
         Composé 255 Composé 256 Composé 257
    Figure imgb1678
    Figure imgb1679
    Figure imgb1680
         Composé 258 Composé 259 Composé 260
    Figure imgb1681
    Figure imgb1682
    Figure imgb1683
         Composé 261 Composé 262 Composé 263
    Figure imgb1684
    Figure imgb1685
    Figure imgb1686
         Composé 264 Composé 265 Composé 266
    Figure imgb1687
    Figure imgb1688
    Figure imgb1689
         Composé 267 Composé 268 Composé 269
    Figure imgb1690
    Figure imgb1691
    Figure imgb1692
         Composé 270 Composé 271 Composé 272
    Figure imgb1693
    Figure imgb1694
    Figure imgb1695
         Composé 273 Composé 274 Composé 275
    Figure imgb1696
    Figure imgb1697
    Figure imgb1698
         Composé 276 Composé 277 Composé 278
    Figure imgb1699
    Figure imgb1700
    Figure imgb1701
         Composé 279 Composé 280 Composé 281
    Figure imgb1702
    Figure imgb1703
    Figure imgb1704
         Composé 282 Composé 285 Composé 286
    Figure imgb1705
    Figure imgb1706
    Figure imgb1707
         Composé 287 Composé 288 Composé 289
    Figure imgb1708
    Figure imgb1709
    Figure imgb1710
         Composé 290 Composé 291 Composé 292
    Figure imgb1711
    Figure imgb1712
    Figure imgb1713
         Composé 293 Composé 294 Composé 295
    Figure imgb1714
    Figure imgb1715
    Figure imgb1716
         Composé 296 Composé 297 Composé 298
    Figure imgb1717
    Figure imgb1718
    Figure imgb1719
         Composé 299 Composé 300 Composé 301
    Figure imgb1720
         Composé 302
  4. Composé de formule (I) selon la revendication 1 où R3 représente un groupement butyle ou pentyle et où R2 et R1 sont tels qu'indiqué ci-avant.
  5. Composé de formule (I) selon la revendication 1 où R3 représente un groupement alkyle en C4-8 substitué par hydroxyle, et où R2 et R1 sont tels qu'indiqué ci-avant.
  6. Composé selon la revendication 5, où R2 représente un groupement alkyle en C1-8, (alkoxy en C1-4)-(alkyle en C1-4), cycloalkyle en C3-7, hétérocycle en C4-7, hétérocycle bicyclique, arylalkyle, hétéroaryle ou hétéroarylalkyle.
  7. Composé selon la revendication 6, qui est choisi parmi les composés suivants :
    Figure imgb1721
    Figure imgb1722
    Figure imgb1723
         Composé 54 Composé 55 Composé 57
    Figure imgb1724
    Figure imgb1725
    Figure imgb1726
         Composé 59 Composé 62 Composé 68
    Figure imgb1727
    Figure imgb1728
    Figure imgb1729
         Composé 72 Composé 73 Composé 92
    Figure imgb1730
    Figure imgb1731
    Figure imgb1732
         Composé 93 Composé 113 Composé 115
    Figure imgb1733
    Figure imgb1734
    Figure imgb1735
         Composé 125 Composé 145 Composé 154
    Figure imgb1736
    Figure imgb1737
    Figure imgb1738
         Composé 165 Composé 186 Composé 187
    Figure imgb1739
    Figure imgb1740
    Figure imgb1741
         Composé 188 Composé 190 Composé 192
    Figure imgb1742
    Figure imgb1743
    Figure imgb1744
         Composé 195 Composé 196 Composé 197
    Figure imgb1745
    Figure imgb1746
    Figure imgb1747
         Composé 198 Composé 204 Composé 205
    Figure imgb1748
    Figure imgb1749
    Figure imgb1750
         Composé 207 Composé 208 Composé 215
    Figure imgb1751
    Figure imgb1752
    Figure imgb1753
         Composé 216 Composé 218 Composé 223
    Figure imgb1754
    Figure imgb1755
    Figure imgb1756
         Composé 228 Composé 229 Composé 231
    Figure imgb1757
    Figure imgb1758
    Figure imgb1759
         Composé 238 Composé 239 Composé 243
    Figure imgb1760
    Figure imgb1761
    Figure imgb1762
         Composé 244 Composé 249 Composé 258
    Figure imgb1763
    Figure imgb1764
    Figure imgb1765
         Composé 261 Composé 266 Composé 268
    Figure imgb1766
    Figure imgb1767
    Figure imgb1768
         Composé 271 Composé 272 Composé 273
    Figure imgb1769
    Figure imgb1770
    Figure imgb1771
         Composé 274 Composé 275 Composé 277
    Figure imgb1772
    Figure imgb1773
    Figure imgb1774
         Composé 278 Composé 279 Composé 280
    Figure imgb1775
    Figure imgb1776
    Figure imgb1777
         Composé 282 Composé 285 Composé 286
    Figure imgb1778
    Figure imgb1779
    Figure imgb1780
         Composé 291 Composé 293 Composé 294
    Figure imgb1781
    Figure imgb1782
    Figure imgb1783
         Composé 296 Composé 297 Composé 298
    Figure imgb1784
    Figure imgb1785
    Figure imgb1786
         Composé 299 Composé 301 Composé 302
  8. Composé de formule (I) selon la revendication 1 où R1 représente un atome d'hydrogène ou un groupement-CH3 et où R2 et R3 sont tels qu'indiqué ci-avant.
  9. Composé de formule (I) selon la revendication 1 où R2 représente un groupement alkyle en C1-3 substitué par aryle, hétérocycle ou hétéroaryle qui est substitué plus avant par alkyle en C1-3, alkoxy en C1-6, ester carboxylique ou amide carboxylique et où R1 et R3 sont tels qu'indiqué ci-avant.
  10. Composition pharmaceutique comprenant un composé de formule (I) ou l'un des sels, tautomères ou ensemble de tautomères, solvates ou polymorphes pharmaceutiquement acceptables de celui-ci selon l'une quelconque des revendications 1 à 9 ainsi qu'un ou plusieurs excipients, diluants ou véhicules pharmaceutiquement acceptables.
  11. Composé de formule (I) ou sel, tautomère ou ensemble de tautomères, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci selon l'une quelconque des revendications 1 à 9, ou composition pharmaceutique selon la revendication 10 pour utilisation comme médicament.
EP17203628.7A 2011-04-08 2012-04-10 Dérivés de la pyrimidine pour le traitement des infections virales Active EP3330257B1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
DK19192173.3T DK3590928T3 (da) 2011-04-08 2012-04-10 Pyrimidinderivater til behandling af virusinfektioner
MEP-2020-84A ME03782B (fr) 2011-04-08 2012-04-10 Dérivés de la pyrimidine pour le traitement des infections virales
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Families Citing this family (200)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2691745T3 (es) 2011-04-08 2018-11-28 Janssen Sciences Ireland Uc Derivados de pirimidina para el tratamiento de infecciones víricas
DK2776439T3 (en) 2011-11-09 2018-10-22 Janssen Sciences Ireland Uc PURINE DERIVATIVES FOR TREATING VIRUS INFECTIONS
EP2794565B1 (fr) 2011-12-21 2017-07-26 Novira Therapeutics Inc. Agents antiviraux de l'hépatite b
DK2872515T3 (en) 2012-07-13 2016-09-19 Janssen Sciences Ireland Uc MACROCYCLIC PURINES FOR TREATING VIRUS INFECTIONS
CA2881057C (fr) 2012-08-28 2020-10-27 Janssen Sciences Ireland Uc Sulfamoyl-arylamides et leur utilisation en tant que medicaments dans le traitement de l'hepatite b
ES2701098T7 (es) * 2012-10-05 2021-02-03 Janssen Sciences Ireland Unlimited Co Derivados de acilaminopirimidina para el tratamiento de infecciones víricas y otras enfermedades
MX386924B (es) 2012-10-10 2025-03-19 Janssen Sciences Ireland Uc Derivados pirrolo[3,2-d]pirimidínicos para el tratamiento de infecciones víricas y otras enfermedades.
US9663474B2 (en) 2012-11-16 2017-05-30 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
KR102300861B1 (ko) 2013-02-21 2021-09-10 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 바이러스 감염의 치료를 위한 2-아미노피리미딘 유도체
JP6466348B2 (ja) 2013-02-28 2019-02-06 ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー スルファモイル−アリールアミドおよびｂ型肝炎を処置するための医薬品としてのその使用
US8993771B2 (en) 2013-03-12 2015-03-31 Novira Therapeutics, Inc. Hepatitis B antiviral agents
WO2014154859A1 (fr) 2013-03-29 2014-10-02 Janssen R&D Ireland Déaza-purinones macrocycliques pour le traitement d'infections virales
HUE033542T2 (en) 2013-04-03 2017-12-28 Janssen Sciences Ireland Uc Their use as medicaments for the treatment of N-phenylcarboxamide derivatives and hepatitis B
TW202126620A (zh) 2013-05-17 2021-07-16 愛爾蘭商健生科學愛爾蘭無限公司 胺磺醯基吡咯醯胺衍生物及其作為用於治療ｂ型肝炎藥物的用途
UA117586C2 (uk) 2013-05-24 2018-08-27 ЯНССЕН САЙЄНСІЗ АЙРЛЕНД ЮСі Похідні піридину для лікування вірусних інфекцій та інших захворювань
MX392130B (es) 2013-06-27 2025-03-21 Janssen Sciences Ireland Uc Derivados de pirrolo[3,2-d]pirimidina para el tratamiento de infecciones víricas y otras enfermedades.
WO2015011281A1 (fr) 2013-07-25 2015-01-29 Janssen R&D Ireland Dérivés de pyrrolamide à substitution glyoxamide et leur utilisation en tant que médicaments pour le traitement de l'hépatite b
ES2836881T3 (es) * 2013-07-30 2021-06-28 Janssen Sciences Ireland Unlimited Co Derivados de tieno[3,2-d]pirimidinas para el tratamiento de infecciones virales
MX368158B (es) 2013-10-23 2019-09-20 Janssen Sciences Ireland Uc Derivados de carboxamida y su uso como medicamentos para el tratamiento de la hepatitis b.
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
JP6553059B2 (ja) 2014-02-05 2019-07-31 ノヴィラ・セラピューティクス・インコーポレイテッド Ｈｂｖ感染の治療のための併用療法
PL3102572T3 (pl) 2014-02-06 2019-04-30 Janssen Sciences Ireland Uc Pochodne sulfamoilopirolamidu i ich zastosowanie jako leki do leczenia wirusowego zapalenia wątroby typu B
US9400280B2 (en) 2014-03-27 2016-07-26 Novira Therapeutics, Inc. Piperidine derivatives and methods of treating hepatitis B infections
BR112017001350A2 (pt) 2014-07-24 2017-11-14 Bayer Cropscience Ag derivados de pirazol fungicidas
SG11201606876RA (en) 2015-03-04 2016-10-28 Gilead Sciences Inc Toll like receptor modulator compounds
EP3271019A1 (fr) 2015-03-19 2018-01-24 Novira Therapeutics Inc. Dérivés d'azocane et d'azonane, et méthodes de traitement d'infections provoquées par le virus de l'hépatite b
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
MA42684A (fr) 2015-08-26 2018-07-04 Gilead Sciences Inc Modulateurs deutérés du récepteur toll
US20180263985A1 (en) 2015-09-15 2018-09-20 Gilead Sciences, Inc. Modulators of toll-like receptors for the treatment of hiv
AR106192A1 (es) 2015-09-29 2017-12-20 Novira Therapeutics Inc Formas cristalinas de un agente antiviral contra la hepatitis b
ES2882671T3 (es) 2015-11-27 2021-12-02 Janssen Sciences Ireland Unlimited Co Indoles heterocíclicos para su uso en infecciones por el virus de la gripe
JP6732915B2 (ja) 2015-12-15 2020-07-29 ギリアード サイエンシーズ， インコーポレイテッド ヒト免疫不全ウイルス中和抗体
BR112018014794A2 (pt) 2016-01-20 2018-12-11 Janssen Sciences Ireland Uc pirimidinas substituídas com arila para uso em infecção pelo vírus influenza
WO2017181141A2 (fr) 2016-04-15 2017-10-19 Novira Therapeutics, Inc. Associations et méthodes comprenant un inhibiteur d'ensemble capside
BR102017010009A2 (pt) 2016-05-27 2017-12-12 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
ES2969239T3 (es) 2016-05-27 2024-05-17 Gilead Sciences Inc Combinación de ledipasvir y sofosbuvir para su uso en el tratamiento de infecciones por el virus de la hepatitis B en humanos
MA45539A (fr) * 2016-07-01 2019-05-08 Janssen Sciences Ireland Unlimited Co Dihydropyranopyrimidines pour le traitement d'infections virales
JOP20190024A1 (ar) 2016-08-26 2019-02-19 Gilead Sciences Inc مركبات بيروليزين بها استبدال واستخداماتها
WO2018045150A1 (fr) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Dérivés de 4,6-diamino-pyrido [3,2-d] pyrimidine en tant que modulateurs du récepteur de type toll
SI3507276T1 (sl) 2016-09-02 2022-01-31 Gilead Sciences, Inc. Spojine modulatorja toličnih receptorjev
SG10202010317VA (en) * 2016-09-29 2020-11-27 Janssen Sciences Ireland Unlimited Co Pyrimidine prodrugs for the treatment of viral infections and further diseases
KR20230010826A (ko) 2016-10-14 2023-01-19 프리시젼 바이오사이언시스 인코포레이티드 B형 간염 바이러스 게놈 내의 인식 서열에 대해 특이적인 조작된 메가뉴클레아제
WO2018106606A1 (fr) * 2016-12-05 2018-06-14 Apros Therapeutics, Inc. Composés de pyrimidine contenant des groupes acides
TWI714820B (zh) 2017-01-31 2021-01-01 美商基利科學股份有限公司 替諾福韋艾拉酚胺(tenofovir alafenamide)之晶型
UY37581A (es) 2017-02-02 2018-08-31 Gilead Sciences Inc Compuestos para el tratamiento de la infección por virus de la hepatitis b
PL3603619T3 (pl) 2017-03-29 2025-11-17 Sumitomo Pharma Co., Ltd. Preparat adjuwantu szczepionkowego
BR102018007822A2 (pt) 2017-04-20 2018-11-06 Gilead Sciences, Inc. composto, métodos para inibir pd-1, pd-l1 e/ou interação de pd-1/pd-l1 e para tratamento de câncer, composição farmacêutica, e, kit para tratamento de ou prevenção de câncer ou uma doença ou condição
TW202024061A (zh) 2017-08-17 2020-07-01 美商基利科學股份有限公司 Hiv蛋白質膜抑制劑之固體形式
AR112412A1 (es) 2017-08-17 2019-10-23 Gilead Sciences Inc Formas de sal de colina de un inhibidor de la cápside del vih
KR102891807B1 (ko) 2017-08-22 2025-12-01 길리애드 사이언시즈, 인코포레이티드 치료 헤테로시클릭 화합물
EP3697755B1 (fr) * 2017-10-20 2021-09-15 SABIC Global Technologies B.V. Nouveau procédé de synthèse pour la préparation de composés dibenzoate, tel que 4-[benzoyl(méthyl)amino]pentane-2-yl dibenzoate
WO2019084060A1 (fr) 2017-10-24 2019-05-02 Silverback Therapeutics, Inc. Conjugués et leurs procédés d'utilisation pour l'administration sélective d'agents immunomodulateurs
EP3700527A4 (fr) * 2017-10-25 2021-03-10 Children's Medical Center Corporation Inhibiteurs de papd5 et leurs méthodes d'utilisation
CA3084667A1 (fr) 2017-12-15 2019-06-20 Silverback Therapeutics, Inc. Conjugue de construction d'anticorps-medicament pour le traitement de l'hepatite
JP7037667B2 (ja) 2017-12-20 2022-03-16 インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエスシーアール，ヴイ．ヴイ．アイ． Ｓｔｉｎｇアダプタータンパク質を活性化するホスホン酸結合を有する３’３’環状ジヌクレオチド
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
RU2020124007A (ru) 2017-12-21 2022-01-21 Сумитомо Дайниппон Фарма Ко., Лтд. Комбинированный препарат, включающий агонист tlr7
WO2019160882A1 (fr) 2018-02-13 2019-08-22 Gilead Sciences, Inc. Inhibiteurs pd -1/pd-l1
WO2019161017A1 (fr) 2018-02-15 2019-08-22 Gilead Sciences, Inc. Dérivés de pyridine et leur utilisation pour le traitement d'une infection par le vih
KR102847339B1 (ko) 2018-02-16 2025-08-19 길리애드 사이언시즈, 인코포레이티드 레트로비리다에 바이러스 감염의 치료에 유용한 치료 화합물을 제조하기 위한 방법 및 중간체
JP7050165B2 (ja) 2018-02-26 2022-04-07 ギリアード サイエンシーズ， インコーポレイテッド Ｈｂｖ複製阻害剤としての置換ピロリジン化合物
TW202415645A (zh) * 2018-03-01 2024-04-16 愛爾蘭商健生科學愛爾蘭無限公司 ２，４－二胺基喹唑啉衍生物及其醫學用途
SG11202007097QA (en) 2018-03-14 2020-08-28 Janssen Sciences Ireland Unlimited Co Capsid assembly modulator dosing regimen
WO2019195181A1 (fr) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Anticorps et leurs fragments qui se lient à la protéine x du virus de l'hépatite b
TWI833744B (zh) 2018-04-06 2024-03-01 捷克科學院有機化學與生物化學研究所 3'3'-環二核苷酸
TW202005654A (zh) 2018-04-06 2020-02-01 捷克科學院有機化學與生物化學研究所 ２，２，─環二核苷酸
TWI818007B (zh) 2018-04-06 2023-10-11 捷克科學院有機化學與生物化學研究所 2'3'-環二核苷酸
US11142750B2 (en) 2018-04-12 2021-10-12 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
KR102591947B1 (ko) 2018-04-19 2023-10-25 길리애드 사이언시즈, 인코포레이티드 Pd-1/pd-l1 억제제
WO2019211799A1 (fr) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue de dinucléotide 2'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle
IL317993B2 (en) 2018-07-03 2025-11-01 Gilead Sciences Inc Antibodies directed against HIV gp120 and methods of use
AU2019297428C1 (en) 2018-07-06 2023-03-23 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
CN112384505B (zh) 2018-07-06 2025-05-27 吉利德科学公司 治疗性的杂环化合物
PE20210642A1 (es) 2018-07-13 2021-03-23 Gilead Sciences Inc Inhibidores de pd-1/pd-l1
CA3103522C (fr) 2018-07-16 2023-11-21 Gilead Sciences, Inc. Inhibiteurs de capsides pour le traitement du vih
AU2019311965B2 (en) 2018-07-23 2026-02-19 Japan Institute For Health Security Composition containing influenza vaccine
WO2020028097A1 (fr) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique
WO2020052738A1 (fr) * 2018-09-11 2020-03-19 F. Hoffmann-La Roche Ag Composés amine pyrazolopyridiniques pour le traitement d'une maladie auto-immune
SG11202101980VA (en) 2018-09-12 2021-03-30 Silverback Therapeutics Inc Methods and composition for the treatment of disease with immune stimulatory conjugates
EP3860717A1 (fr) 2018-10-03 2021-08-11 Gilead Sciences, Inc. Dérivés d'imidozopyrimidine
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
EP3873608A1 (fr) 2018-10-31 2021-09-08 Gilead Sciences, Inc. Composés 6-azabenzimidazole substitués ayant une activité inhibitrice de hpk1
EP4371987B9 (fr) 2018-10-31 2025-11-26 Gilead Sciences, Inc. Composés de 6-azabenzimidazole substitués utilisés en tant qu'inhibiteurs de hpk1
BR112021015577A2 (pt) 2019-02-08 2021-10-05 Research & Business Foundation Sungkyunkwan University Complexo-colesterol agonista do receptor toll-like 7 ou 8 e uso do mesmo
AU2020223865A1 (en) 2019-02-22 2021-07-15 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2020176505A1 (fr) 2019-02-25 2020-09-03 Gilead Sciences, Inc. Agonistes de protéine kinase c
WO2020176510A1 (fr) 2019-02-25 2020-09-03 Gilead Sciences, Inc. Agonistes de protéine kinase c
CN113574063B (zh) 2019-03-07 2025-03-18 捷克共和国有机化学与生物化学研究所 3’3’-环二核苷酸及其前药
WO2020178768A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Analogue du dinucléotide 3'3'-cyclique comprenant un nucléotide modifié par cyclopentanyle utilisé en tant que modulateur de sting
WO2020178769A1 (fr) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides cycliques en 2'3' et leurs promédicaments
KR20240151256A (ko) 2019-03-22 2024-10-17 길리애드 사이언시즈, 인코포레이티드 가교된 트리시클릭 카르바모일피리돈 화합물 및 그의 제약 용도
TW202210480A (zh) 2019-04-17 2022-03-16 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TWI751517B (zh) 2019-04-17 2022-01-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
EP3959197A4 (fr) 2019-04-24 2022-10-12 Children's Medical Center Corporation Inhibiteurs de papd5 et leurs procédés d'utilisation
BR112021021454A2 (pt) 2019-05-06 2021-12-21 Janssen Sciences Ireland Unlimited Co Derivados de amida úteis no tratamento da infecção por hbv ou doenças induzidas por hbv
TWI762925B (zh) 2019-05-21 2022-05-01 美商基利科學股份有限公司 鑑別對使用gp120 v3聚醣導向之抗體的治療敏感之hiv病患的方法
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
WO2020255042A1 (fr) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combinaison de vaccins contre le virus de l'hépatite b (vhb) et d'un dérivé de pyrimidine
WO2020255035A1 (fr) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combinaison de vaccins contre le virus de l'hépatite b (vhb) et de dérivés de pyrimidine
WO2020255038A1 (fr) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Association de vaccins contre le virus de l'hépatite b (vhb) et de dérivés de pyridopyrimidine
US20220241402A1 (en) 2019-06-18 2022-08-04 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and quinazoline derivatives
MX2021015533A (es) 2019-06-19 2022-02-10 Silverback Therapeutics Inc Anticuerpos anti-mesotelina e inmunoconjugados de los mismos.
CN114245807B (zh) 2019-06-25 2025-05-02 吉利德科学公司 Flt3l-fc融合蛋白和使用方法
TWI879779B (zh) 2019-06-28 2025-04-11 美商基利科學股份有限公司 類鐸受體調節劑化合物的製備方法
CN112174823B (zh) * 2019-07-01 2023-12-01 南京富润凯德生物医药有限公司 一种合成2,2-二甲基-3-氧杂环丁酮的中间体及其制备方法和应用
AU2020315598B2 (en) 2019-07-16 2024-12-12 Gilead Sciences, Inc. HIV vaccines and methods of making and using
WO2021011891A1 (fr) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Formulations à action prolongée de ténofovir alafénamide
US20220296619A1 (en) 2019-08-19 2022-09-22 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
HRP20241379T1 (hr) 2019-09-30 2024-12-20 Gilead Sciences, Inc. Cjepiva za hbv i postupci za liječenje hbv
WO2021067644A1 (fr) 2019-10-01 2021-04-08 Silverback Therapeutics, Inc. Polythérapie comprenant des conjugués immunostimulants
PH12022550835A1 (en) 2019-10-18 2023-07-03 Forty Seven Inc Combination therapies for treating myelodysplastic syndromes and acute myeloid leukemia
NZ786589A (en) 2019-10-31 2025-03-28 Forty Seven Llc Anti-cd47 and anti-cd20 based treatment of blood cancer
TWI778443B (zh) 2019-11-12 2022-09-21 美商基利科學股份有限公司 Mcl1抑制劑
CA3157275C (fr) 2019-11-26 2026-02-10 Gilead Sciences, Inc. Inhibiteurs de capside pour la prevention du vih
US12410418B2 (en) 2019-12-06 2025-09-09 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
CN115362003B (zh) 2019-12-24 2024-03-22 卡尔那生物科学株式会社 二酰基甘油激酶调节化合物
TWI890283B (zh) 2020-02-14 2025-07-11 美商基利科學股份有限公司 結合ccr8之抗體及融合蛋白及其用途
US11179473B2 (en) 2020-02-21 2021-11-23 Silverback Therapeutics, Inc. Nectin-4 antibody conjugates and uses thereof
CN115666637A (zh) 2020-03-02 2023-01-31 蛋白科技先锋 基于病原体细胞壁骨架的模拟活病原体的纳米粒子及其制备方法
KR102987126B1 (ko) 2020-03-20 2026-07-07 길리애드 사이언시즈, 인코포레이티드 4'-c-치환된-2-할로-2'-데옥시아데노신 뉴클레오시드의 프로드러그 및 이의 제조 및 사용 방법
JP7564888B2 (ja) 2020-05-01 2024-10-09 ギリアード サイエンシーズ， インコーポレイテッド Ｃｄ７３阻害性２，４－ジオキソピリミジン化合物
EP4153181B1 (fr) 2020-05-21 2026-07-29 Gilead Sciences, Inc. Compositions pharmaceutiques contenant du bictégravir
TWI858267B (zh) 2020-06-25 2024-10-11 美商基利科學股份有限公司 用於治療hiv之蛋白殼抑制劑
KR20230047361A (ko) 2020-07-01 2023-04-07 아르스 파마슈티컬스 인크. 항-asgr1 항체 접합체 및 이의 용도
EP4194008A4 (fr) 2020-08-04 2025-01-08 Progeneer Inc. Ensemble adjuvant à action cinétique
WO2022031021A1 (fr) 2020-08-04 2022-02-10 성균관대학교산학협력단 Vaccin à arnm comprenant un adjuvant permettant un contrôle cinétique
US20230277525A1 (en) 2020-08-04 2023-09-07 Progeneer Inc Conjugate of functional drug and toll-like receptor 7 or 8 agonist of which active site is temporarily inactivated and use thereof
LT4192474T (lt) 2020-08-07 2025-11-25 Fosfonamidų nukleotidų analogų provaistai ir jų farmacinis panaudojimas
TWI815194B (zh) 2020-10-22 2023-09-11 美商基利科學股份有限公司 介白素2-Fc融合蛋白及使用方法
CN116437958A (zh) 2020-11-11 2023-07-14 吉利德科学公司 鉴定对采用gp120 CD4结合位点导向的抗体的疗法敏感的HIV患者的方法
WO2022217022A1 (fr) 2021-04-10 2022-10-13 Profoundbio Us Co. Agents de liaison à folr1, conjugués de ceux-ci et leurs procédés d'utilisation
TW202302145A (zh) 2021-04-14 2023-01-16 美商基利科學股份有限公司 ＣＤ４７／ＳＩＲＰα結合及ＮＥＤＤ８活化酶Ｅ１調節次單元之共抑制以用於治療癌症
CA3216459A1 (fr) 2021-04-23 2022-10-27 Profoundbio Us Co. Anticorps anti-cd70, leurs conjugues et leurs procedes d'utilisation
US20240269142A1 (en) 2021-05-13 2024-08-15 Gilead Sciences, Inc. COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS
WO2022245671A1 (fr) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Méthodes d'utilisation de protéines de fusion flt3l-fc
JP7651018B2 (ja) 2021-06-23 2025-03-25 ギリアード サイエンシーズ， インコーポレイテッド ジアシルグリセロールキナーゼ調節化合物
EP4359413A1 (fr) 2021-06-23 2024-05-01 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
MX2023014762A (es) 2021-06-23 2024-01-15 Gilead Sciences Inc Compuestos moduladores de diacilglicerol quinasa.
CN117355531A (zh) 2021-06-23 2024-01-05 吉利德科学公司 二酰基甘油激酶调节化合物
TW202320857A (zh) 2021-07-06 2023-06-01 美商普方生物製藥美國公司 連接子、藥物連接子及其結合物及其使用方法
EP4423078A1 (fr) 2021-10-28 2024-09-04 Gilead Sciences, Inc. Dérivés de pyridine-3(2h)-one
PE20241186A1 (es) 2021-10-29 2024-06-03 Gilead Sciences Inc Compuestos de cd73
FI4440702T3 (fi) 2021-12-03 2025-08-08 Gilead Sciences Inc Terapeuttisia yhdisteitä hiv-virusinfektiota varten
AU2022399845B2 (en) 2021-12-03 2026-03-26 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
AU2022403012B2 (en) 2021-12-03 2026-02-12 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
US20230203202A1 (en) 2021-12-08 2023-06-29 Dragonfly Therapeutics, Inc. Proteins binding nkg2d, cd16 and 5t4
WO2023107954A1 (fr) 2021-12-08 2023-06-15 Dragonfly Therapeutics, Inc. Anticorps ciblant 5t4 et leurs utilisations
CN118488948A (zh) 2021-12-22 2024-08-13 吉利德科学公司 Ikaros锌指家族降解剂及其用途
US20240124412A1 (en) 2021-12-22 2024-04-18 Gilead Sciences, Inc. Ikaros zinc finger family degraders and uses thereof
CA3248911A1 (fr) 2022-01-28 2023-08-03 Gilead Sciences, Inc. Inhibiteurs de poly(adénosine diphosphate-ribose) polymérase 7
PL4245756T3 (pl) 2022-03-17 2025-02-17 Gilead Sciences, Inc. Środki degradujące palec cynkowy z rodziny ikaros i ich zastosowania
AU2023240346A1 (en) 2022-03-24 2024-09-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers
TWI876305B (zh) 2022-04-05 2025-03-11 美商基利科學股份有限公司 用於治療結腸直腸癌之組合療法
TWI856796B (zh) 2022-04-06 2024-09-21 美商基利科學股份有限公司 橋聯三環胺甲醯基吡啶酮化合物及其用途
EP4511127A1 (fr) 2022-04-21 2025-02-26 Gilead Sciences, Inc. Composés modulateurs de kras g12d
WO2024006929A1 (fr) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Composés cd73
US20240034724A1 (en) 2022-07-01 2024-02-01 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
CA3259040A1 (fr) 2022-07-12 2024-01-18 Gilead Sciences, Inc. Polypeptides immunogènes du vih et vaccins et utilisations de ceux-ci
CN116120282B (zh) * 2022-08-04 2024-02-20 苏州系统医学研究所 具有ev71和/或cva16病毒抑制活性的化合物及其应用
CN119768183A (zh) 2022-08-26 2025-04-04 吉利德科学公司 用于广泛中和抗体的给药和安排方案
US20240091351A1 (en) 2022-09-21 2024-03-21 Gilead Sciences, Inc. FOCAL IONIZING RADIATION AND CD47/SIRPa DISRUPTION ANTICANCER COMBINATION THERAPY
WO2024076915A1 (fr) 2022-10-04 2024-04-11 Gilead Sciences, Inc. Analogues de 4'-thionucléosides et leur utilisation pharmaceutique
EP4638436A1 (fr) 2022-12-22 2025-10-29 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2024215754A1 (fr) 2023-04-11 2024-10-17 Gilead Sciences, Inc. Composés modulateurs de kras
EP4698174A1 (fr) 2023-04-19 2026-02-25 Gilead Sciences, Inc. Schéma posologique d'inhibiteur de capside
PE20260121A1 (es) 2023-04-21 2026-01-16 Gilead Sciences Inc Inhibidores de prmt5 y usos de los mismos
WO2024249573A1 (fr) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Formes solides de composés utiles dans le traitement du vih
TW202448483A (zh) 2023-05-31 2024-12-16 美商基利科學股份有限公司 用於ｈｉｖ之治療性化合物
JP2026522894A (ja) 2023-06-30 2026-07-09 ギリアード サイエンシーズ， インコーポレイテッド Ｋｒａｓ調節化合物
AU2024297978A1 (en) 2023-07-26 2026-02-05 Gilead Sciences, Inc. Parp7 inhibitors
CN121568935A (zh) 2023-07-26 2026-02-24 吉利德科学公司 Parp7抑制剂
CN122295099A (zh) 2023-07-28 2026-06-26 吉利德科学公司 用于治疗和预防hiv的来那卡帕韦的每周方案
AU2023462614A1 (en) 2023-08-23 2026-03-19 Gilead Sciences, Inc. Dosing regimen of hiv capsid inhibitor
US20250109147A1 (en) 2023-09-08 2025-04-03 Gilead Sciences, Inc. Kras g12d modulating compounds
EP4774280A1 (fr) 2023-09-08 2026-07-15 Gilead Sciences, Inc. Composés de modulation de kras g12d
AR133955A1 (es) 2023-09-26 2025-11-19 Profoundbio Us Co Agentes de unión a ptk7, conjugados de éstos y métodos de uso de los mismos
IL327206A (en) 2023-10-11 2026-05-01 Gilead Sciences Inc Bridged tricyclic carbamoylpyridone compounds and their uses
KR20260093341A (ko) 2023-10-11 2026-06-19 길리애드 사이언시즈, 인코포레이티드 가교 트리시클릭 카르바모일피리돈 화합물 및 이의 용도
AU2024360779A1 (en) 2023-10-11 2026-04-16 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025096589A1 (fr) 2023-11-03 2025-05-08 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2025110816A1 (fr) 2023-11-23 2025-05-30 프로지니어 주식회사 Polythérapie de traitement anticancéreux avec un agoniste du récepteur de type toll 7 ou 8 ayant un site actif temporairement inactivé pour traiter le cancer
WO2025137245A1 (fr) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Formes solides d'inhibiteurs de l'intégrase du vih
US20250230168A1 (en) 2023-12-22 2025-07-17 Gilead Sciences, Inc. Azaspiro wrn inhibitors
TW202547866A (zh) 2024-01-10 2025-12-16 丹麥商珍美寶股份有限公司 Ｓｌｉｔｒｋ６結合劑、其共軛物及使用彼之方法
WO2025181219A1 (fr) 2024-02-29 2025-09-04 Genmab A/S Agents de liaison bispécifiques egfr et c-met, conjugués de ceux-ci et leurs procédés d'utilisation
WO2025184447A1 (fr) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Compositions pharmaceutiques comprenant des inhibiteurs de l'intégrase du vih
US20250333424A1 (en) 2024-03-01 2025-10-30 Gilead Sciences, Inc. Antiviral compounds
WO2025184452A1 (fr) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Formes solides d'inhibiteurs de l'intégrase du vih
WO2025240246A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies avec de la ribavirine
US20250345390A1 (en) 2024-05-13 2025-11-13 Gilead Sciences, Inc. Combination therapies
TW202608468A (zh) 2024-05-13 2026-03-01 美商基利科學股份有限公司 組合療法
WO2025240242A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies avec ribavirine
WO2025245003A1 (fr) 2024-05-21 2025-11-27 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2025260028A1 (fr) 2024-06-14 2025-12-18 Gilead Sciences, Inc. Compositions pharmaceutiques comprenant des inhibiteurs de l'intégrase du vih
US20260098049A1 (en) 2024-08-12 2026-04-09 Gilead Sciences, Inc. Kras modulating compounds
WO2026076265A1 (fr) 2024-10-03 2026-04-09 Gilead Sciences, Inc. Thérapie de combinaison comprenant des composés de carbamoylpyridone tricycliques pontés et des inhibiteurs de la p-glycoprotéine
US20260130893A1 (en) 2024-10-21 2026-05-14 Gilead Sciences, Inc. Prmt5 inhibitors and uses thereof
WO2026136515A1 (fr) 2024-12-19 2026-06-25 Gilead Sciences, Inc. Inhibiteurs de parp7

Family Cites Families (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2610889B2 (ja) 1987-09-03 1997-05-14 日本臓器製薬株式会社 新規架橋アデニン誘導体
JP4667543B2 (ja) 1996-07-03 2011-04-13 大日本住友製薬株式会社 新規プリン誘導体
PL332040A1 (en) 1996-08-28 1999-08-16 Pfizer Substitution 6,5-heterobicyclic derivatives
AU733316B2 (en) 1996-10-04 2001-05-10 Kyorin Pharmaceutical Co. Ltd. Pyrazolopyridylpyridazinone derivatives and process for preparing the same
AR012634A1 (es) 1997-05-02 2000-11-08 Sugen Inc Compuesto basado en quinazolina, composicion famaceutica que lo comprende, metodo para sintetizarlo, su uso, metodos de modulacion de la funcion deserina/treonina proteinaquinasa con dicho compuesto y metodo in vitro para identificar compuestos que modulan dicha funcion
US6339089B2 (en) 1997-08-13 2002-01-15 Fujirebio Inc. Pyrimidine nucleus-containing compound and a medicament containing the same for a blood oxygen partial pressure amelioration, and a method for preparing the same
JP4375901B2 (ja) 1997-11-28 2009-12-02 大日本住友製薬株式会社 新規な複素環化合物
TW572758B (en) 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
US6187777B1 (en) 1998-02-06 2001-02-13 Amgen Inc. Compounds and methods which modulate feeding behavior and related diseases
ATE245641T1 (de) 1998-02-17 2003-08-15 Tularik Inc Antivirale pyrimidinderivate
US6110929A (en) 1998-07-28 2000-08-29 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
JP4342007B2 (ja) 1998-08-10 2009-10-14 大日本住友製薬株式会社 キナゾリン誘導体
JP4315300B2 (ja) 1998-08-10 2009-08-19 大日本住友製薬株式会社 新規なキナゾリン誘導体
ES2221414T3 (es) 1998-08-27 2004-12-16 Sumitomo Pharmaceuticals Company, Limited Derivados de pirimidina.
US6583148B1 (en) * 1999-04-08 2003-06-24 Krenitsky Pharmaceuticals, Inc. Neurotrophic substituted pyrimidines
CA2323008C (fr) 1999-10-11 2005-07-12 Pfizer Inc. Composes pharmaceutiques actifs
WO2002088079A2 (fr) 2001-05-01 2002-11-07 Bristol-Myers Squibb Company Inhibiteurs doubles de pde 7 et pde 4
WO2003055890A1 (fr) 2001-12-21 2003-07-10 Bayer Pharmaceuticals Corporation Composes derives de thienopyrimidine utilises comme inhibiteurs de la prolylpeptidase, inducteurs d'apoptose et agents de traitement anticancereux
TW200407143A (en) 2002-05-21 2004-05-16 Bristol Myers Squibb Co Pyrrolotriazinone compounds and their use to treat diseases
US7091232B2 (en) 2002-05-21 2006-08-15 Allergan, Inc. 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds
AU2003242252A1 (en) 2002-06-07 2003-12-22 Kyowa Hakko Kogyo Co., Ltd. Bicyclic pyrimidine derivatives
CA2497765A1 (fr) 2002-09-27 2004-04-08 Sumitomo Pharmaceuticals Co., Ltd. Nouveau compose d'adenine et son application
US8455458B2 (en) 2002-10-16 2013-06-04 Arthrodynamic Technologies, Animal Health Division, Inc. Composition and method for treating connective tissue damage
US7410975B2 (en) 2003-06-20 2008-08-12 Coley Pharmaceutical Group, Inc. Small molecule toll-like receptor (TLR) antagonists
EP1667694B1 (fr) 2003-09-05 2010-04-28 Anadys Pharmaceuticals, Inc. Ligands tlr7 destines au traitement du virus de l'hepatite c
WO2005092892A1 (fr) 2004-03-26 2005-10-06 Dainippon Sumitomo Pharma Co., Ltd. Compose 8-oxoadenine
BRPI0509258A8 (pt) 2004-03-26 2019-01-22 Astrazeneca Ab composto de 8-oxoadenina 9-substituída
WO2007084413A2 (fr) 2004-07-14 2007-07-26 Ptc Therapeutics, Inc. Procedes de traitement de l’hepatite c
AU2005271161B2 (en) 2004-08-10 2011-05-12 Janssen Pharmaceutica N.V. HIV inhibiting 1,2,4-triazin-6-one derivatives
KR100915481B1 (ko) 2004-11-09 2009-09-03 에프. 호프만-라 로슈 아게 아미노퀴나졸린 화합물
US7498409B2 (en) 2005-03-24 2009-03-03 Schering Corporation Screening assay for TLR7, TLR8 and TLR9 agonists and antagonists
EA200702235A1 (ru) 2005-05-04 2008-04-28 Пфайзер Лимитед Производные 2-амидо-6-амино-8-оксопурина в качестве модуляторов toll-подобных рецепторов для лечения рака и вирусных инфекций, таких как гепатит с
AR054122A1 (es) 2005-05-12 2007-06-06 Tibotec Pharm Ltd Pirido[2,3-d]pirimidas utiles como inhibidores de hcv, y metodos para la preparacion de las mismas
US7994360B2 (en) 2005-05-16 2011-08-09 Xtl Biopharmaceuticals Ltd. Benzofuran compounds
TW201402124A (zh) 2005-08-19 2014-01-16 Array Biopharma Inc 作為類鐸受體（ｔｏｌｌ-ｌｉｋｅ ｒｅｃｅｐｔｏｒ）調節劑之８-經取代苯并氮雜呯
ES2612890T3 (es) 2005-09-01 2017-05-19 F. Hoffmann-La Roche Ag Diaminopirimidinas como moduladores de P2X3 y P2X2/3
JPWO2007034881A1 (ja) 2005-09-22 2009-03-26 大日本住友製薬株式会社 新規アデニン化合物
WO2007056208A2 (fr) 2005-11-02 2007-05-18 Cytovia, Inc. N-arylalkyl-thienopyrimidin-4-amines et analogues en tant qu'activateurs de caspases et inducteurs d'apoptose et utilisation de ceux-ci
WO2007063934A1 (fr) 2005-12-02 2007-06-07 Mitsubishi Tanabe Pharma Corporation Compose heterocyclique alicyclique
AU2007216247A1 (en) 2006-02-17 2007-08-23 Pfizer Limited 3 -deazapurine derivatives as TLR7 modulators
WO2008009078A2 (fr) 2006-07-20 2008-01-24 Gilead Sciences, Inc. Dérivés de la quinazoline tri-substitués en 4,6-dl et en 2,4,6 utilisables pour traiter les infections virales
US8673929B2 (en) 2006-07-20 2014-03-18 Gilead Sciences, Inc. 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives and pharmaceutical compositions useful for treating viral infections
CA2671845C (fr) 2006-12-07 2015-03-24 Genentech, Inc. Composes inhibiteurs de la phosphoinositide 3-kinase et procedes d'utilisation
US8101595B2 (en) 2006-12-20 2012-01-24 Istituto di Ricerche di Biologia Molecolare P. Angletti SpA Antiviral indoles
EP2510946B1 (fr) 2007-02-07 2015-08-05 The Regents of The University of California Conjugués d'agonistes synthétiques de tlr et leurs utilisations
JP2008222557A (ja) 2007-03-08 2008-09-25 Kotobuki Seiyaku Kk ピロロ［３，２−ｄ］ピリミジン誘導体及びこれを有効成分とする医薬組成物
EP2132209B8 (fr) 2007-03-19 2014-04-16 AstraZeneca AB Composés 8-oxo-adenine 9 substitué comme modulateurs du récepteur de type toll (tlr7)
EP2138497A4 (fr) 2007-03-20 2012-01-04 Dainippon Sumitomo Pharma Co Nouveau composé d'adénine
TW200902018A (en) 2007-03-20 2009-01-16 Dainippon Sumitomo Pharma Co Novel adenine compound
ATE518840T1 (de) 2007-05-22 2011-08-15 Boehringer Ingelheim Int Benzimidazolonchymasehemmer
EP2170888B1 (fr) 2007-06-29 2015-04-22 Gilead Sciences, Inc. Dérivés de purine et leur utilisation comme modulateurs du récepteur de type toll-7
CN101842098A (zh) 2007-08-10 2010-09-22 基因实验室技术有限公司 用于治疗病毒感染的含氮的二环化学实体
BRPI0815979A2 (pt) 2007-08-28 2017-06-13 Irm Llc compostos e composições com inibidores de quinase, bem como uso dos mesmos
WO2009030998A1 (fr) 2007-09-05 2009-03-12 Coley Pharmaceutical Group, Inc. Composés pyrimidine utilisés comme agonistes du récepteur de type toll (tlr)
PE20091236A1 (es) * 2007-11-22 2009-09-16 Astrazeneca Ab Derivados de pirimidina como immunomoduladores de tlr7
CN101910177B (zh) 2007-12-24 2013-08-28 泰博特克药品公司 作为丙型肝炎病毒抑制剂的大环吲哚
WO2009099650A2 (fr) 2008-02-07 2009-08-13 Carson Dennis A Traitement des maladies de la vessie avec un activateur de tlr7
CN102014911A (zh) 2008-04-28 2011-04-13 默沙东公司 Hcv ns3蛋白酶抑制剂
US8946239B2 (en) 2008-07-10 2015-02-03 Duquesne University Of The Holy Spirit Substituted pyrrolo, -furano, and cyclopentylpyrimidines having antimitotic and/or antitumor activity and methods of use thereof
UY31982A (es) 2008-07-16 2010-02-26 Boehringer Ingelheim Int Derivados de 1,2-dihidropiridin-3-carboxamidas n-sustituidas
CA2732437C (fr) 2008-08-01 2017-11-21 Ventirx Pharmaceuticals, Inc. Formulations d'agoniste des recepteurs de type toll et leur utilisation
AU2010250923A1 (en) * 2009-05-21 2011-11-17 Astrazeneca Ab Novel pyrimidine derivatives and their use in the treatment of cancer and further diseases
US8637525B2 (en) 2009-07-31 2014-01-28 Bristol-Myers Squibb Company Compounds for the reduction of beta-amyloid production
TWI468402B (zh) 2009-07-31 2015-01-11 必治妥美雅史谷比公司 降低β－類澱粉生成之化合物
CN102666537A (zh) 2009-10-20 2012-09-12 艾格尔生物制药股份有限公司 治疗黄病毒科病毒感染的氮杂吲唑
BR112012009329A2 (pt) 2009-10-22 2016-06-07 Gilead Sciences Inc derivados de purina ou deazapurina úteis para o tratamento de infecções virais (inter alia)
KR101094446B1 (ko) 2009-11-19 2011-12-15 한국과학기술연구원 단백질 키나아제 저해활성을 가지는 2,4,7-치환된 티에노［3,2-ｄ］피리미딘 화합물
JP2013032290A (ja) 2009-11-20 2013-02-14 Dainippon Sumitomo Pharma Co Ltd 新規縮合ピリミジン誘導体
DE102010040233A1 (de) 2010-09-03 2012-03-08 Bayer Schering Pharma Aktiengesellschaft Bicyclische Aza-Heterocyclen und ihre Verwendung
US20120082658A1 (en) 2010-10-01 2012-04-05 Ventirx Pharmaceuticals, Inc. Methods for the Treatment of Allergic Diseases
WO2012066335A1 (fr) 2010-11-19 2012-05-24 Astrazeneca Ab Composés phénol en tant qu'agonistes du récepteur 7 de type toll
WO2012067269A1 (fr) 2010-11-19 2012-05-24 Dainippon Sumitomo Pharma Co., Ltd. Composés aminoalcoxyphényle et leur utilisation dans le traitement de maladies
ES2691745T3 (es) * 2011-04-08 2018-11-28 Janssen Sciences Ireland Uc Derivados de pirimidina para el tratamiento de infecciones víricas
PL2709989T3 (pl) 2011-05-18 2018-06-29 Janssen Sciences Ireland Uc Pochodne chinazoliny do leczenia infekcji wirusowych i dalszych chorób
DK2776439T3 (en) 2011-11-09 2018-10-22 Janssen Sciences Ireland Uc PURINE DERIVATIVES FOR TREATING VIRUS INFECTIONS
EA039373B1 (ru) 2012-02-08 2022-01-19 Янссен Сайенсиз Айрлэнд Юси Производные пиперидино-пиримидина для лечения вирусных инфекций
SG11201406584TA (en) 2012-04-24 2014-11-27 Vertex Pharma Dna-pk inhibitors
DK2872515T3 (en) 2012-07-13 2016-09-19 Janssen Sciences Ireland Uc MACROCYCLIC PURINES FOR TREATING VIRUS INFECTIONS
JP6302906B2 (ja) 2012-08-10 2018-03-28 ヤンセン・サイエンシズ・アイルランド・ユーシー ウイルス感染および他の疾患を治療するためのアルキルピリミジン誘導体
EP2712866A1 (fr) 2012-10-01 2014-04-02 Centre National de la Recherche Scientifique (CNRS) Dérivés de 1,2,4-triazine pour le traitement d'infections virales
ES2701098T7 (es) 2012-10-05 2021-02-03 Janssen Sciences Ireland Unlimited Co Derivados de acilaminopirimidina para el tratamiento de infecciones víricas y otras enfermedades
MX386924B (es) 2012-10-10 2025-03-19 Janssen Sciences Ireland Uc Derivados pirrolo[3,2-d]pirimidínicos para el tratamiento de infecciones víricas y otras enfermedades.
US9663474B2 (en) 2012-11-16 2017-05-30 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
KR102300861B1 (ko) 2013-02-21 2021-09-10 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 바이러스 감염의 치료를 위한 2-아미노피리미딘 유도체
WO2014154859A1 (fr) 2013-03-29 2014-10-02 Janssen R&D Ireland Déaza-purinones macrocycliques pour le traitement d'infections virales
UA117586C2 (uk) 2013-05-24 2018-08-27 ЯНССЕН САЙЄНСІЗ АЙРЛЕНД ЮСі Похідні піридину для лікування вірусних інфекцій та інших захворювань
MX392130B (es) 2013-06-27 2025-03-21 Janssen Sciences Ireland Uc Derivados de pirrolo[3,2-d]pirimidina para el tratamiento de infecciones víricas y otras enfermedades.
ES2836881T3 (es) 2013-07-30 2021-06-28 Janssen Sciences Ireland Unlimited Co Derivados de tieno[3,2-d]pirimidinas para el tratamiento de infecciones virales
EP3166938A4 (fr) 2014-07-11 2018-01-17 Northwestern University Échafaudages 2-imidazolyl-pyrimidine en tant qu'inhibiteurs puissants et sélectifs de l'oxyde nitrique synthase neuronale
MA45539A (fr) 2016-07-01 2019-05-08 Janssen Sciences Ireland Unlimited Co Dihydropyranopyrimidines pour le traitement d'infections virales

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

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CA2832685A1 (fr) 2012-10-11
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US20200061059A1 (en) 2020-02-27
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